Mitochondrial dysfunction in Brooks–Wisniewski–Brown syndrome

Morava, Éva; Rodenburg, Richard J.; Hol, F.A.; Meırleır, Linda De; Seneca, Sara; Busch, Rebekka; Heuvel, Lambertus van den; Smeitink, Jan A.M.

doi:10.1002/ajmg.a.31117

Cited by 5 publications

(6 citation statements)

References 14 publications

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“…In addition, there were clinical discrepancies between the affected probands and the BWB patients described in the literature. The boys described by Brooks et al presented with spastic diplegia, optic and cerebellar atrophy, and entropion, which were not noted in our cases; the majority of patients reported by Morava exhibited regression, seizures, and corpus callosum hypogenesis that were not present in the patients described in the current study. Given that BWB syndrome is an extremely rare disorder and exhibits a high degree of clinical heterogeneity, it is possible that BWB could be genetically heterogeneous and that the phenotype of our patients represents a BWB‐like disorder, caused by mutation in a gene other than HUWE1 .…”

Section: Discussioncontrasting

confidence: 56%

“…18 To date, there is no evidence of HS6ST2 involvement in Mendelian diseases. [19][20][21][22] ID, speech delay, and severe myopia in a context of mild dysmorphia were the specific key features supporting the similarity. Moreover, the three BWB patients described by Morava et al 21 presented with increased blood lactate values in infancy, similar to the affected twins.…”

Section: Discussionmentioning

confidence: 65%

“…The Face2Gene phenotyping tool identified a slight similarity of the phenotype of the affected boys with that of BWB syndrome, a condition described by Brooks et al, Morava et al, and Friez et al ID, speech delay, and severe myopia in a context of mild dysmorphia were the specific key features supporting the similarity. Moreover, the three BWB patients described by Morava et al presented with increased blood lactate values in infancy, similar to the affected twins.…”

Section: Discussionmentioning

confidence: 99%

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A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins

et al. 2018

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X‐linked intellectual disability (XLID) refers to a clinically and genetically heterogeneous neurodevelopmental disorder, in which males are more heavily affected than females. Among the syndromic forms of XLID, identified by additional clinical signs as part of the disease spectrum, the association between XLID and severe myopia has been poorly characterized. We used whole exome sequencing (WES) to study two Italian male twins presenting impaired intellectual function and adaptive behavior, in association with severe myopia and mild facial dysmorphisms. WES analysis detected the novel, maternally inherited, mutation c.916G > C (G306R) in the X‐linked heparan sulfate 6‐O‐sulfotransferase 2 (HS6ST2) gene. HS6ST2 transfers sulfate from adenosine 3′‐phosphate, 5′‐phosphosulfate to the sixth position of the N‐sulphoglucosamine residue in heparan sulfate (HS) proteoglycans. Low HS sulfation levels are associated with defective optic disc and stalk morphogenesis during mammalian visual system development. The c.916G>C variant affects the HS6ST2 substrate binding site, and its effect was considered “deleterious” by in‐silico tools. An in‐vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity. Taken together, the results suggest that mutant HS6ST2 is possibly involved in the development of myopia and cognitive impairment, characteristics of the probands reported here.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

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A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins

et al. 2018

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“…It has been reported that mitochondrial function is essential for normal growth in pulmonary epithelial-like cells in culture (9). Compromised mitochondrial oxidative phosphorylation has been implicated in pathogenesis of genetic diseases presenting with developmental and growth restriction of different organs (10). Clearly, well-functioning mitochondria are needed to convert nutritional substrates into energy to maintain growth and development.…”

mentioning

confidence: 99%

Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

Ratner¹,

Starkov²,

Matsiukevich³

et al. 2009

Am J Respir Cell Mol Biol

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This study investigated whether mitochondrial dysfunction contributes to alveolar developmental arrest in a mouse model of bronchopulmonary dysplasia (BPD). To induce BPD, 3-day-old mice were exposed to 75% O 2 . Mice were studied at two time points of hyperoxia (72 h or 2 wk) and after 3 weeks of recovery in room air (RA). A separate cohort of mice was exposed to pyridaben, a complex-I (C-I) inhibitor, for 72 hours or 2 weeks. Alveolarization was quantified by radial alveolar count and mean linear intercept methods. Pulmonary mitochondrial function was defined by respiration rates, ATP-production rate, and C-I activity. At 72 hours, hyperoxic mice demonstrated significant inhibition of C-I activity, reduced respiration and ATP production rates, and significantly decreased radial alveolar count compared with controls. Exposure to pyridaben for 72 hours, as expected, caused significant inhibition of C-I and ADP-phosphorylating respiration. Similar to hyperoxic littermates, these pyridaben-exposed mice exhibited significantly delayed alveolarization compared with controls. At 2 weeks of exposure to hyperoxia or pyridaben, mitochondrial respiration was inhibited and associated with alveolar developmental arrest. However, after 3 weeks of recovery from hyperoxia or 2 weeks after 72 hours of exposure to pyridaben alveolarization significantly improved. In addition, there was marked normalization of C-I and mitochondrial respiration. The degree of hyperoxia-induced pulmonary simplification and recovery strongly (r 2 5 0.76) correlated with C-I activity in lung mitochondria. Thus, the arrest of alveolar development induced by either hyperoxia or direct inhibition of mitochondrial oxidative phosphorylation indicates that bioenergetic failure to maintain normal alveolar development is one of the fundamental mechanisms responsible for BPD.

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“…Castro-Gago et al 8 carried out an analysis of muscle biopsies and described light microscopic morphology and ultrastructural alterations typical of mitochondrial disorders, and low levels of complexes III and IV of the mitochondrial respiratory chain in congenital hydranencephalic-hydrocephalic syndrome. Morava et al 9 reported mitochondrial dysfunction in Brooks-Wisniewski-Brown syndrome with a significantly compromised of mitochondrial oxidative phosphorylation. These findings raised the possibility that at least some cases of congenital hydranencephalic-hydrocephalic syndrome may be due to alterations in the mitochondrial respiratory chain.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria morphopathological changes in human congenital hydrocephalus, Arnold-Chiari malformation and postmeningitis hydrocephalus. An electron microscopic study

Castejón¹

2018

JNSK

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Cerebral cortical biopsies of 16 patients with clinical diagnosis of congenital malformations, Arnold-Chiari malformation and postmeningitis hydrocephalus were studied to establish mitochondrial morphopathological alterations. Cortical biopsies obtained in the surgical room were immediately processed by conventional technique for transmission electron microscopy. Three injured mitochondrial morphological patterns were found: Swollen clear mitochondria, swollen dense mitochondria, and dark degenerated mitochondria were frequently observed in hydrocephalic parenchyma. Swollen clear mitochondria exhibited low electron dense matrix, enlarged intracristal space and continuity of outer and inner mitochondrial membranes. Swollen dense mitochondria showed high electron dense matrix and swollen fragmented cristae. Dense degenerated mitochondria displayed overall high electron density of matrix and mitochondrial membranes. Such injured mitochondrial pattern are mainly related with nerve cell death and considered markers of lethal nerve cell injury.

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Mitochondrial dysfunction in Brooks–Wisniewski–Brown syndrome

Cited by 5 publications

References 14 publications

A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins

A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins

Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

Mitochondria morphopathological changes in human congenital hydrocephalus, Arnold-Chiari malformation and postmeningitis hydrocephalus. An electron microscopic study

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